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ETS2-dependent control in cardiomyocyte ischemia/reperfusion injury

ETS2-dependent control in cardiomyocyte ischemia/reperfusion injury
ETS2 依赖性控制心肌细胞缺血/再灌注损伤
批准号:
10674020
负责人:
THOMAS G GILLETTE
金额:
$61.79万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-01 至 2026-07-31

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中文摘要
翻译
项目摘要/摘要 心力衰竭是世界各地发病率和死亡率的主要原因,也是 心力衰竭伴射血分数降低(HFrEF)是冠状动脉疾病。有丝分裂原激活 蛋白激酶(MAPK)是一种重要的信号转导通路,在这两种细胞中都发挥着核心作用 生长和细胞死亡。MAPK通路的MEK1-ERK1/2分支已被证明促进两者 心脏的生理性和病理性生长,以及防止细胞凋亡后死亡 缺血再灌注(I/R)损伤。我们之前已经证明了转录因子ETS2,a E26转换特异序列(ETS)结构域家族的成员,被磷酸化并被激活 ERK1/2在肥大刺激中的作用。展望未来,我们的初步数据显示心肌细胞- ETS2的特异性丢失导致I/R和永久结扎对缺血性损伤的易感性增加 (心肌梗塞)心力衰竭模型。连接蛋白43(Cx43),主要的缝隙连接通道- 在心肌细胞中形成蛋白,已被认为在缺血性损伤和缺血性损伤中都发挥作用 预适应。我们的初步数据显示,ETS2激活了Cx43的转录,而Cx43是 在没有ETS2的情况下下调监管。我们将测试ERK1/2/ETS2通路保护 抗I/R损伤的作用部分是通过上调Cx43来实现的。 目的1:探讨ERK1/2-ETS2通路在脑I/R损伤中的作用。我们的初步数据显示 ETS2保护I/R损伤的一种模型。我们将使用损失和收益来确认和延长这一点 在体内和体外的功能接近。我们将跟踪ERK激活ETS2的时间和响应 每一个都在急剧和长期的重塑中。 目的:探讨ETS2在脑I/R损伤中对Cx43表达和功能的影响。我们的数据 提示Cx43在脑缺血损伤中起保护作用。我们的初步数据还表明,ETS2是 Cx43基因表达的直接转录调节因子。我们将使用以下工具来确认和扩展这些发现 功能损失法和功能增益法。我们还将确定ETS2在Cx43介导的 IPC中的心脏保护。 目的3:确定心脏条件下ETS2的下游靶点和相互作用因子 压力。我们将使用RNAseq和ChIPseq来分析全基因组心脏基因的表达,以确定 ETS2下游基因在急性和长期I/R损伤中的靶点。我们将使用免疫沉淀和 质谱学揭示新的蛋白质相互作用。
英文摘要
Project Summary/Abstract Heart failure is a leading cause of morbidity and mortality around the world, and the leading cause of heart failure with reduced ejection fraction (HFrEF) is coronary artery disease. The mitogen-activated protein kinases (MAPK) are an essential signal transduction cascade that play a central role in both cell growth and cell death. The MEK1-ERK1/2 branch of the MAPK pathway has been shown to promote both physiologic and pathologic growth in the heart, as well as protect against apoptotic cell death after ischemia/reperfusion (I/R) injury. We have previously demonstrated that the transcription factor ETS2, a member of E26 transformation-specific sequence (ETS)-domain family, is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation. Going forward, our preliminary data reveal that cardiomyocyte- specific loss of ETS2 results in increased susceptibility to ischemic injury in both I/R and permanent ligation (myocardial infarction) models of heart failure. Connexin43 (Cx43), the predominant gap junction channel- forming protein in cardiomyocytes, has been suggested to play a role in both ischemic damage and ischemic preconditioning. Our preliminary data show that ETS2 activates Cx43 transcription and that Cx43 is downregulated in the absence of ETS2. We will test the hypothesis that the ERK1/2/ETS2 pathway protects against I/R injury in part through the upregulation of Cx43. Aim 1: To determine the role of the ERK1/2-ETS2 pathway in I/R injury. Our preliminary data suggest a model in which ETS2 protects against I/R injury. We will confirm and extend this using loss- and gain-of- function approaches in vivo and in vitro. We will track the timing of ETS2 activation by ERK and the response of each acutely and in long-term remodeling. Aim 2: To determine the impact of ETS2 on Cx43 expression and function in I/R injury. Our data suggest that Cx43 plays a protective role in ischemic injury. Our preliminary data also suggest that ETS2 is a direct transcriptional regulator of Cx43 gene expression. We will confirm and extend these findings using both loss- and gain-of-function approaches. We will also determine the role of ETS2 in Cx43-mediated cardioprotection in IPC. Aim 3: To determine the downstream targets and interactors of ETS2 under conditions of cardiac stress. We will profile genome-wide cardiac gene expression using RNAseq and ChIPseq to determine ETS2 downstream gene targets in both acute and long-term I/R injury. We will use immunoprecipitation and mass spectrometry to unveil novel protein interactions.
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ETS2-dependent control in cardiomyocyte ischemia/reperfusion injury
  • 批准号:
    10501545
  • 项目类别:
  • 资助金额:
    $61.79万
  • 财政年份:
    2022
  • 负责人:
    THOMAS G GILLETTE
  • 依托单位:
Molecular Mechanisms of HFpEF-associated Atrial Fibrillation
  • 批准号:
    10545081
  • 项目类别:
  • 资助金额:
    $41.0万
  • 财政年份:
    2021
  • 负责人:
    THOMAS G GILLETTE
  • 依托单位:
Molecular Mechanisms of HFpEF-associated Atrial Fibrillation
  • 批准号:
    10322371
  • 项目类别:
  • 资助金额:
    $41.0万
  • 财政年份:
    2021
  • 负责人:
    THOMAS G GILLETTE
  • 依托单位:
Molecular Mechanisms of HFpEF-associated Atrial Fibrillation
  • 批准号:
    10097363
  • 项目类别:
  • 资助金额:
    $40.92万
  • 财政年份:
    2021
  • 负责人:
    THOMAS G GILLETTE
  • 依托单位:
海外基金